The gastrointestinal tract, which comprises the stomach, duodenum, small intestine etc., is very important for digesting foodstuffs fed through the oral cavity. The contractile motility of the gastrointestinal tract is indispensable for effective digestion of foodstuffs. In the case of healthy humans and animals, contractile motion is controlled by the autonomic nervous system as well as by gastrointestinal hormones and occurs with regularity not only in the digestive state, but also in the interdigestive state. In the latter state, the gastrointestinal tract is throughly cleaned before a subsequent meal as the contractile motility is transferred from the stomach to the small intestine through the duodenum.
The contractile motion of the gastrointestinal tract occuring naturally in the digestive state, i.e. immediately after a meal, shows continuous contraction waves, while the contractile motion occuring naturally in the interdigestive state shows intermittent waves with an interval of about 100 minutes. It is also known that a relationship exists between induction of contractile motion in the gastrointestinal tract and the concentration of the gastrointestinal hormone motilin in the blood. The concentration of this hormone in the blood decreases during feeding.
In the interdigestive state, contractile motion of the gastrointestinal tract correlates with a high concentration of motilin in the blood with reference to the reports by Zen Itoh, "Iden" (1979, Japanese version), Vol. 33, No. 12, pages 29-33; and Zen Itoh et al., Scand. J. Gastroent. (1976), 11, Suppl. 39. 93-110.
Agents for inducing contractile motility of the gastrointestinal tract are of interest for the treatment of humans suffering from poor function of the gastrointestinal tract, in order to improve the motility of the gastrointestinal tract and overall health.
It is known that motilin is capable of inducing motility of the gastrointestinal tract. J. C. Brown et al. extracted motilin from the duodenal mucosa of pig and reported that this substance is a peptide comprising 22 amino acids (J. C. Brown et al: Gastroent., 50, 333-339, 1966). The synthesis of motilin is also known (see, for example, B. Wunsch et al: Z. Naturforsch., 28C, 235-240, 1973). However, the supply of motilin extracted from natural souces and synthetic motilin is insufficient to satisfy practical needs.
One aspect of the present invention is based on the surprizing discovery that both erythromycin and 9-dihydroerythromycin and their pharmaceutically acceptable salts and derivatives are capable of inducing contractile motility of the gastrointestinal tract of humans and animals, and may be used to prepare pharmaceutical compositions for this purpose. However, erythromycin and 9-dihydroerythromycin are well-recognized antibiotics. From the point of view of maintaining the effectiveness of erythromycin and 9-dihydroerythromycin as antibiotics, it may not be desired to use these compounds for an alternative medical purpose.
Thus, another aspect of the present invention is based upon the further discovery that 8,9-anhydroerythromycin 6,9-hemiketals and anhydroerythromycins are also capable of inducing contractile motility of the gastrointestinal tract.